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OBJECTIVES:

Thymomas are relatively rare tumors. In this study, we investigated the clinical features of patients who underwent surgical resection for thymoma.

PATIENTS AND METHODS:

This study clinicopathologically evaluated 54 consecutive patients who underwent a surgical resection of thymoma in our department between 1994 and 2006.

RESULTS:

A complete resection was performed in 52 patients, while two patients underwent an incomplete resection due to pleural dissemination. Combined resection with adjacent organs was performed for the lung (n=6), pericardium (n=5), and large vessels (brachiocephalic vein in three, superior vena cava in two). The concomitant autoimmune diseases were observed in 20 patients (37%), and they included myasthenia gravis in 17 patients, macroglobulinemia in one, pemphigus vulgaris in one, and stiff person syndrome in one patient. The histologic types of the World Health Organization classification diagnosed as type A in four patients, type AB in 14, type B1 in eight, type B2 in 15, and type B3 in 11. There were 27, 17, eight, and two patients with Masaoka stages I, II, III, and IV, respectively. Four patients died, and the causes of death included recurrence of thymoma in two, gastric carcinoma in one, and respiratory failure due to myasthenia gravis in one patient. The overall survival rate at 10 years was 94.6% in patients with stages I and II disease and 77.1% in patients with stages III and IV disease.

CONCLUSIONS:

Long-term survival can be expected not only for patients at early stages, as well as for patients with stages III and IV disease if surgical resection is completed macroscopically.

Pemphigus is a chronic, muco-cutaneous autoimmune blistering disorder; two main variants being pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV is the most common subtype, varying between 75 to 92% of total pemphigus patients. Although no community based studies are undertaken to estimate the incidence of pemphigus in India, it is relatively common. A questionnaire based survey in Thrissur district of south India estimated pemphigus incidence to be 4.4 per million population. Mortality due to pemphigus has decreased remarkably with the aggressive and widespread use of corticosteroids, prior to which it was as high as 90%. High dose corticosteroids were once used in combination with other immunosuppressants with good improvement, but such high doses of corticosteroids were often associated with severe side effects, and were responsible for the death of nearly 10% of the patients. With the aim of reducing the adverse effects of long term, high dose steroid administration dexamethasone cyclophosphamide pulse (DCP) therapy was introduced in 1984. Since then DCP or oral corticosteroids with or without adjuvant immunosuppressants (azathioprine, cyclophosphamide, mycophenolatemofetil, and cyclosporine) have been the corner-stone of therapy for these disorders in India. Despite the benefits associated with DCP therapy compared to high dose oral steroids, it cannot be denied that even DCP therapy with or without adjuvants can lead to numerous adverse events, which account for majority of deaths in pemphigus. Moreover there are few patients who fail to improve with these conventional treatments or have contraindications for their usage. Thus there has been a constant search for newer therapeutic modalities in pemphigus. Rituximab (Reditux. Dr. Reddy’s, Hyderabad, India and MabThera TM , Roche, Basel, Switzerland), a monoclonal chimeric IgG1 antibody targeting the B cell specific cell-surface antigen CD20, is one such newer novel therapy for pemphigus (an off-label indication for its use. It has so far been approved by FDA for use only in CD 20+ B cell non-Hodgkin’s lymphoma, treatment resistant rheumatoid arthritis, Wegener’s granulomatosis and microscopic polyangiitis).

There is currently no consensus on the optimal dosage and schedule of rituximab in treatment of pemphigus. The various treatment protocols followed include:

Lymphoma protocol- Most commonly followed protocol. Rituximab is administered at a dose of 375mg/m 2 body surface area weekly for four weeks.

Rheumatoid arthritis protocol- Two doses of rituximab 1g is administered at an interval of 15 days. Increasingly used by dermatologists and is the protocol currently followed in our institute. Advantage over the lymphoma protocol include less cost and fewer infusions.

Combination therapy- Rituximab has been used in combination with IVIG, immunoadsorption and dexamethasone pulse therapy

Long-term rituximab treatment with regular infusions every 4 or 12 weeks following an induction cycle of infusions every week

Background: Desquamative gingivitis refers to a clinical manifestation associated with several mucocutaneous disorders. The most common are mucous membrane pemphigoid, pemphigus vulgaris and lichen planus. Their specific diagnosis is better established by histopathological and immunofluorescence evaluation.

Objective: To examine cases of desquamative gingivitis using reflectance confocal microscopy and compare the findings with those of normal gingiva. Moreover, confocal microscopy findings in desquamative gingivitis were compared to conventional histopathology of the biopsied lesions, in order to establish criteria for this non-invasive diagnostic technique.

Methods: Cases suspected of mucous membrane pemphigoid, pemphigus vulgaris and lichen planus were included, totalizing twenty-five cases. Reflectance confocal microscopy was performed the gingival of a healthy person and on gingival lesions. All lesions were biopsied in order to perform a reflectance confocal microscopy- histopathologic correlation.

Results: Reflectance confocal microscopy exam of the gingival lesions suspected of mucous membrane pemphigoid revealed a separation at the level of dermal-epidermal junction, filled with small bright structures interpreted as blood cells. Histopathological and immunofluorescence aspects confirmed the diagnosis. For pemphigus vulgaris, reflectance confocal microscopy aspects were of intraepithelial cleft with round detached cells interpreted as acantholytic keratinocytes, similar to the histopathological features. Hyperkeratosis and spongiosis associated with infiltration of inflammatory cells, recognized as small bright cells intermingling the honeycomb keratinocyte epithelial structure, were seen in lichen planus. Mild bright round structures interpreted as necrotic keratinocytes and mild bright stellate structures, interpreted as melanophages in the dermis were also seen. These features were present in histopathology, confirming the diagnosis of lichen planus.

Conclusion: We propose the use of reflectance confocal microscopy as a useful tool to help distinguish between the three most common causes of desquamative gingivitis.

Results Both groups were similar in age, gender, disease duration, and DAI. Primary endpoint: By ITT and TCA, the mean DAI improved in both groups with no significant difference between them. The difference became significant for the last trimester (3 months; ITT:P = 0.033, TCA: P = 0.045). Secondary endpoint: The total steroid dose decreased significantly in both groups, with no significant difference between them, except for the last trimester (ITT: P = 0.011, TCA: P = 0.035). The mean daily steroid dose decreased gradually in both groups becoming statistically significant in favour of azathioprine, in the last trimester, especially at 12th months (ITT: P = 0.002, TCA:P = 0.005). Complete remission was significant at 12 months only for TCA (AZA/Control: 53.6%/39.9%, P = 0.043).

Limitations Sample size was rather small to demonstrate all differences. Other limitations include the choice of primary and secondary endpoints and the unavailability to measure thiopurine methyltransferase activity.

Pemphigus foliaceus, the most common autoimmune skin condition in dogs and cats, is characterized by pustules, erosions, and crusts. In this article, we focus on the diagnosis and treatment of pemphigus foliaceus in dogs and cats.

The signs of an attack on keratinocyte adhesion structures are clinically evident. When the tight bonds between superficial keratinocytes are affected, it manifests as vesicles and pustules. When the tight bonds between basilar keratinocytes and the skin’s basement membrane are affected, it manifests as bullae (large blisters) and ulcers.

In pemphigus foliaceus in people, the most common target of autoantibodies is the desmoglein 1 (DSG1) glycoprotein in the desmosome. The autoantibody response primarily involves IgG (IgG4 subclass). Initial studies in dogs with pemphigus foliaceus only rarely detected an IgG autoantibody response, but more recent work using different substrates in indirect immunofluorescence testing confirms that IgG autoantibodies are important in canine pemphigus foliaceus. However, DSG1 is not commonly targeted in pemphigus foliaceus in dogs ; it is not yet known which part of the desmosome is targeted in most canine pemphigus foliaceus cases. Early immunoblotting studies revealed that the target was a 148 kDa or 160 kDa protein. Immunoelectron microscopy shows that the site of autoantibody binding is in the extracellular region of the desmosome.

Genetic factors can influence the development of pemphigus foliaceus. In dogs, it is more frequently diagnosed in two breeds with closely related genotypes, Akitas and chows. Pemphigus foliaceus has also been reported in littermates. No breed disposition has been noted in feline pemphigus foliaceus. Sex and age appear to be unrelated to the development of pemphigus foliaceus in dogs and cats. The age of onset is variable and ranges from 1 to 16 years in dogs and less than 1 year of age4 to up to 17 years of age in cats.

Background Pemphigus foliaceus (PF) is a chronic cutaneous autoimmune blistering disease that is characterized by superficial blistering of the skin, and according to the current perspective is caused by autoantibodies directed against desmoglein (Dsg) 1.

Objectives To examine early acantholysis in the skin of patients with PF at an ultrastructural level.

Methods Two Nikolsky-negative (N−), five Nikolsky-positive (N+) and two lesional skin biopsies from immunoserologically defined patients with PF were studied by light and electron microscopy.

Results We found no abnormalities in N− PF skin, whereas all the N+ skin biopsies displayed intercellular widening between desmosomes, a decreased number of desmosomes and hypoplastic desmosomes in the lower epidermal layers. Acantholysis was present in two of five N+ biopsies, but only in the upper epidermal layers. The lesional skin biopsies displayed acantholysis in the higher epidermal layers. Hypoplastic desmosomes were partially (pseudo-half-desmosomes) or completely torn off from the opposing cell.

Conclusion We propose the following mechanism for acantholysis in PF: initially PF IgG causes a depletion of nonjunctional Dsg1, leading to intercellular widening between desmosomes starting in the lower layers and spreading upwards. Depletion of nonjunctional Dsg1 impairs the assembly of desmosomes, resulting in hypoplastic desmosomes and a decreased number of desmosomes. In addition, antibodies might promote disassembly of desmosomes. In the upper layers of the epidermis, where Dsg3 is not expressed and cannot compensate for Dsg1 loss, ongoing depletion of Dsg1 will finally result in a total disappearance of desmosomes and subsequent acantholysis.

MedWire News: Researchers have identified the primary target of the autoantibodies found in the serum of patients with the blistering skin disorder pemphigus vulgaris (PV).

PV patients develop antibodies against the proteins desmoglein (DSG)1 and 3, which help epidermal cells stick together and maintain the integrity of the skin, causing painful blistering on the skin and mucus membranes.

Giovanna Zambruno (Istituto Dermopatico dell’Immacolata, Rome, Italy) and colleagues found that the cis-adhesive interface of the DSG3 extracellular domain (EC)1 is the main target of the PV autoantibody (A)224 generated in the serum of patients with PV.

Existing therapies for the condition target the whole immune system, but this can cause problems with side effects and can result in patients being vulnerable to infections.

To pinpoint the trigger of the autoantibody production in PV more specifically, Zambruno and team isolated 15 immunoglobulin (Ig)G antibodies specific for DSG3 from two patients with the disorder.

Of these, three disrupted layers of skin cells in the laboratory and two were pathogenic when expressed in a murine passive transfer model.

The epitopes recognized by the pathogenic PV antibodies were isolated to the DSG3 EC1 and EC2 subdomains and a specific serologic assay was used to pinpoint the target of the PVA224 as being the cis-adhesive interface on EC1.

The researchers suggest that the autoreactivity seen in PV is due to somatic mutations that are generated by an antigen other than DSG3, as binding to DSG3 disappeared when the somatic mutations reverted to the germline sequence.

“The identification of an immunodominant region targeted by pathogenic antibodies has implications for diagnosis of PV and opens new perspectives toward the establishment of therapeutic approaches for treatment of PV patients,” write Zambruno and team in the Journal of Clinical Investigation.

“Finally, the germlined version of the PV autoantibodies may lead to the identification of the antigens that eventually lead to development of this life-threatening disease.”

This study aimed to highlight the importance of routine screening for hyperglycemia and to develop a standardized, evidence-based approach for the management of pemphigus patients on prolonged systemic corticosteroid (CS) therapy. A cross-sectional study was conducted in two university-affiliated teaching hospitals using a referred sample of 200 patients with a confirmed diagnosis of pemphigus vulgaris, pemphigus foliaceus, or mucous membrane pemphigoid. All patients were receiving systemic CS therapy. A total of 150 patients responded to the survey. Six participants were excluded and 144 were included. The main outcome measure was blood glucose level to detect hyperglycemia. New-onset hyperglycemia was identified in 40% of patients who received CS therapy. None of the expected variables, including age, body mass index, family history of diabetes, corticosteroid dose, and duration of corticosteroid therapy, were independently associated with new-onset hyperglycemia. These findings indicate that the prevalence of CS-induced hyperglycemia in pemphigus patients is 40% and that in patients with pemphigus or MMP, CS therapy is associated with a markedly increased risk for hyperglycemia (odds ratio = 10.7, 95% confidence interval 1.38–83.50) compared with that of patients with the same diseases who do not receive CS therapy.

Background Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal blistering diseases caused by autoantibodies targeting desmoglein (Dsg) adhesion proteins. Previous studies have shown an IgG4 > IgG1 predominance of anti-Dsg antibodies in pemphigus; however, no studies have examined total serum IgG4 levels in pemphigus. IgG4 is induced by chronic antigen stimulation, which could occur with persistent skin blistering and potentially elevate the total serum IgG4 relative to other IgG subclasses in patients with pemphigus.

Objectives The primary aim of the study was to quantitate total and Dsg-specific IgG subclasses in patients with pemphigus.

Methods IgG subclasses and Dsg-specific IgG1 and IgG4 were quantitated in patients with PV and PF, and in sera from age-matched controls using a subclass enzyme-linked immunosorbent assay. The effectiveness of IgG4 depletion in blocking IgG pathogenicity in PV was determined using a keratinocyte dissociation assay.

Results Dsg-specific antibodies comprised a median of 7·1% and 4·2% of total IgG4 in patients with PV and PF, respectively, with eightfold and fourfold enrichment in IgG4 vs. IgG1. Total serum IgG4, but not other IgG subclasses, was enriched in patients with PV and PF compared with age-matched controls (P = 0·004 and P = 0·005, respectively). IgG4 depletion of PV sera reduced pathogenicity in a keratinocyte dissociation assay and showed that affinity-purified IgG4 is more pathogenic than other serum IgG fractions.

Conclusions Dsg-specific autoantibodies are significantly enriched in IgG4, which may explain the enrichment of total serum IgG4 in some patients with pemphigus. By preferentially targeting autoimmune rather than beneficial immune antibodies, IgG4-targeted therapies may offer safer treatment options for pemphigus.

Background Promoter polymorphisms of the macrophage migration inhibitory factor gene are associated with increased production of macrophage migration inhibitory factor. Elevated levels of macrophage migration inhibitory factor have been observed in the sera of patients with pemphigus vulgaris. More than this, macrophage migration inhibitory factor promoter gene polymorphism has been found to confer increased risk of susceptibility to chronic inflammatory diseases.

Objective We investigated whether there is an association between promoter polymorphism of the macrophage migration inhibitory factor gene and pemphigus vulgaris.

Methods One hundred and six patients with pemphigus vulgaris, and a control panel of one hundred healthy volunteers were genotyped for a single nucleotide polymorphism identified in the 5′-flanking region at the position −173 of the gene, using polymerase chain reaction–restriction fragment length analysis.

Results We found a notably high prevalence of C/C genotype in our nation but no significant difference was observed between patients and controls.

Conclusion The result of this study using a large and well documented trial of patients showed that macrophage migration inhibitory factor −173G-C polymorphism is not associated with pemphigus vulgaris; but as the role of macrophage migration inhibitory factor in the inflammatory process has not been delineated in detail and the prevalence of C/C genotype is notably higher in our nation, this finding merits more consideration.

About IPPF

The International Pemphigus & Pemphigoid Foundation’s most important objectives are to provide patients and doctors worldwide with information about pemphigus and pemphigoid, and to provide patients and their caregivers much needed comfort and support so they can continue to live active, productive lives.Read more »